Early-onset pancreatic cancer and associated metabolic risk factors in the Middle East and North Africa: A 20-year analysis of the Global Burden of Disease Study.

BACKGROUND AND OBJECTIVE: Early-onset pancreatic cancer (EOPC) is associated with poor prognosis and high disease burden. Metabolic risk factors such as diabetes and obesity are considered risk factors of EOPC. Recently, there has been an increasing number of EOPCs worldwide. However, the analysis of EOPC, including its metabolic risk factors, in the Middle East and North Africa (MENA) region has not been fully addressed. METHODS: Data from the Global Burden of Disease Study between 2000 and 2019 was used to analyze the prevalence, incidence, deaths and disability-adjusted life years (DALYs) associated with EOPC and its metabolic risk factors. The analysis further categorized the data based on countries, income status and sex and examined the annual percentage change (APC). RESULTS: Approximately 2800 cases, 2400 deaths and 114,000 DALYs were attributable to EOPC in the MENA region. The incidence (APC + 3.42%), death (APC + 0.73%) and DALYs (APC + 3.23%) rates of EOPC increased. In addition, the death and DALY rates of EOPC attributable to obesity and diabetes increased. High and upper-middle-income countries exhibited a higher burden of EOPC than lower-income countries. CONCLUSION: Over the past two decades, the burden of EOPC and its associated metabolic risk factors has increased. There is an urgent need for region-wide policy development, including screening methods and risk factor reduction, to mitigate the high and rising burden of EOPC in the MENA region.

A genome-wide association study identifies a possible role for cannabinoid signalling in the pathogenesis of diabetic kidney disease.

Diabetic kidney disease (DKD), also known as diabetic nephropathy, is the leading cause of renal impairment and end-stage renal disease. Patients with diabetes are at risk for DKD because of poor control of their blood glucose, as well as nonmodifiable risk factors including age, ethnicity, and genetics. This genome-wide association study (GWAS) was conducted for the first time in the Emirati population to investigate possible genetic factors associated with the development and progression of DKD. We included data on 7,921,925 single nucleotide polymorphism (SNPs) in 258 cases of type 2 diabetes mellitus (T2DM) who developed DKD and 938 control subjects with T2DM who did not develop DKD. GWAS suggestive results (P < 1 × 10-5) were further replicated using summary statistics from three cohorts with T2DM-induced DKD (Bio Bank Japan data, UK Biobank, and FinnGen Project data) and T1DM-induced DKD (UK-ROI cohort data from Belfast, UK). When conducting a multiple linear regression model for gene-set analyses, the CNR2 gene demonstrated genome-wide significance at 1.46 × 10-6. SNPs in CNR2 gene, encodes cannabinoid receptor 2 or CB2, were replicated in Japanese samples with the leading SNP rs2501391 showing a Pcombined = 9.3 × 10-7, and odds ratio = 0.67 in association with DKD associated with T2DM, but not with T1DM, without any significant association with T2DM itself. The allele frequencies of our cohort and those of the replication cohorts were in most cases markedly different. In addition, we replicated the association between rs1564939 in the GLRA3 gene and DKD in T2DM (P = 0.016, odds ratio = 0.54 per allele C). Our findings suggest evidence that cannabinoid signalling may be involved in the development of DKD through CB2, which is expressed in different kidney regions and known to be involved in insulin resistance, inflammation, and the development of kidney fibrosis.

Monogenic diabetes variants in Emirati women with gestational diabetes are associated with risk of non-autoimmune diabetes within 5 years after pregnancy.

Aims: To investigate the prevalence of pathogenic variants in monogenic diabetes genes in Emirati women with gestational diabetes (GDM) and examine the risk of developing hyperglycemia during follow-up in carriers and non-carriers. Methods: Female patients with GDM (n = 370) were identified. Selected monogenic diabetes genes, GCK, HNF1A, HNF4A, HNF1B, INS, ABCC8 and KCNJ1I, were examined by sequencing and identified variants were classified. Anthropometrics and subsequent diagnosis of diabetes were extracted from hospital records. Median follow-up time was 6-years. Results: A total of 34 variants were detected. Seven women (2%) were carriers of pathogenic variants in GCK, HNF1A, INS, ABCC8 or KCNJ11. A significantly larger fraction of women carrying pathogenic variants were diagnosed with any form of hyperglycemia or diabetes postpartum (risk ratio = 1.8 (1.1-2.9), p = 0.02) or 2.5 (1.3-4.8; p = 0.009), respectively) and they had a shorter disease-free period after GDM compared to women without such variants. There were no significant associations between carrying pathogenic variants and anthropometric measures or C-peptide. Conclusions: Pathogenic variants were found in known monogenic diabetes genes in two percent of Emirati women with GDM, allowing for precision medicine utilisation in these women both during and outside pregnancy. Carriers were at an increased risk of being diagnosed with hyperglycemia or type 2 diabetes mellitus within 5 years after pregnancy.

Fine-Scale Genetic Structure in the United Arab Emirates Reflects Endogamous and Consanguineous Culture, Population History, and Geography.

The indigenous population of the United Arab Emirates (UAE) has a unique demographic and cultural history. Its tradition of endogamy and consanguinity is expected to produce genetic homogeneity and partitioning of gene pools while population movements and intercontinental trade are likely to have contributed to genetic diversity. Emiratis and neighboring populations of the Middle East have been underrepresented in the population genetics literature with few studies covering the broader genetic history of the Arabian Peninsula. Here, we genotyped 1,198 individuals from the seven Emirates using 1.7 million markers and by employing haplotype-based algorithms and admixture analyses, we reveal the fine-scale genetic structure of the Emirati population. Shared ancestry and gene flow with neighboring populations display their unique geographic position while increased intra- versus inter-Emirati kinship and sharing of uniparental haplogroups, reflect the endogamous and consanguineous cultural traditions of the Emirates and their tribes.

Low Detection Rates of Genetic FH in Cohort of Patients With Severe Hypercholesterolemia in the United Arabic Emirates.

Background: Programs to screen for Familial hypercholesterolemia (FH) are conducted worldwide. In Western societies, these programs have been shown to be cost-effective with hit/detection rates of 1 in 217-250. Thus far, there is no published data on genetic FH in the Gulf region. Using United Arab Emirates as a proxy for the Gulf region, we assessed the prevalence of genetically confirmed FH in the Emirati population sample. Materials and Methods: We recruited 229 patients with LDL-C >95th percentile and employed a customized next generation sequencing pipeline to screen canonical FH genes (LDLR, APOB, PCSK9, LDLRAP1). Results: Participants were characterized by mean total cholesterol and low-density lipoprotein cholesterol (LDL-c) of 6.3 ± 1.1 and 4.7 ± 1.1 mmol/L respectively. Ninety-six percent of the participants were using lipid-lowering medication with mean corrected LDL-c values of 10.0 ± 3.0 mmol/L 15 out of 229 participants were found to suffer from genetically confirmed FH. Carriers of causal genetic variants for FH had higher on-treatment LDL-c compared to those without causal variants (5.7 ± 1.5 vs 4.7 ± 1.0; p = 3.7E-04). The groups did not differ regarding high-density lipoprotein cholesterol, triglycerides, body mass index, blood pressure, glucose, and glycated haemoglobin. Conclusion: This study reveals a low 7% prevalence of genetic FH in Emiratis with marked hypercholesterolemia as determined by correcting LDL-c for the use of lipid-lowering treatment. The portfolio of mutations identified is, to a large extent, unique and includes gene duplications. Our findings warrant further studies into origins of hypercholesterolemia in these patients. This is further supported by the fact that these patients are also characterized by high prevalence of type 2 diabetes (42% in the current study cohort) which already puts them at an increased risk of atherosclerotic cardiovascular disease. These results may also be useful in public health initiatives for FH cascade screening programs in the UAE and maybe the Gulf region.

FAM20A mutations can cause enamel-renal syndrome (ERS).

Enamel-renal syndrome (ERS) is an autosomal recessive disorder characterized by severe enamel hypoplasia, failed tooth eruption, intrapulpal calcifications, enlarged gingiva, and nephrocalcinosis. Recently, mutations in FAM20A were reported to cause amelogenesis imperfecta and gingival fibromatosis syndrome (AIGFS), which closely resembles ERS except for the renal calcifications. We characterized three families with AIGFS and identified, in each case, recessive FAM20A mutations: family 1 (c.992G>A; g.63853G>A; p.Gly331Asp), family 2 (c.720-2A>G; g.62232A>G; p.Gln241_Arg271del), and family 3 (c.406C>T; g.50213C>T; p.Arg136* and c.1432C>T; g.68284C>T; p.Arg478*). Significantly, a kidney ultrasound of the family 2 proband revealed nephrocalcinosis, revising the diagnosis from AIGFS to ERS. By characterizing teeth extracted from the family 3 proband, we demonstrated that FAM20A(-/-) molars lacked true enamel, showed extensive crown and root resorption, hypercementosis, and partial replacement of resorbed mineral with bone or coalesced mineral spheres. Supported by the observation of severe ectopic calcifications in the kidneys of Fam20a null mice, we conclude that FAM20A, which has a kinase homology domain and localizes to the Golgi, is a putative Golgi kinase that plays a significant role in the regulation of biomineralization processes, and that mutations in FAM20A cause both AIGFS and ERS.

Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis.

Disorders of sex development (DSD), ranging in severity from mild genital abnormalities to complete sex reversal, represent a major concern for patients and their families. DSD are often due to disruption of the genetic programs that regulate gonad development. Although some genes have been identified in these developmental pathways, the causative mutations have not been identified in more than 50% 46,XY DSD cases. We used the Affymetrix Genome-Wide Human SNP Array 6.0 to analyse copy number variation in 23 individuals with unexplained 46,XY DSD due to gonadal dysgenesis (GD). Here we describe three discrete changes in copy number that are the likely cause of the GD. Firstly, we identified a large duplication on the X chromosome that included DAX1 (NR0B1). Secondly, we identified a rearrangement that appears to affect a novel gonad-specific regulatory region in a known testis gene, SOX9. Surprisingly this patient lacked any signs of campomelic dysplasia, suggesting that the deletion affected expression of SOX9 only in the gonad. Functional analysis of potential SRY binding sites within this deleted region identified five putative enhancers, suggesting that sequences additional to the known SRY-binding TES enhancer influence human testis-specific SOX9 expression. Thirdly, we identified a small deletion immediately downstream of GATA4, supporting a role for GATA4 in gonad development in humans. These CNV analyses give new insights into the pathways involved in human gonad development and dysfunction, and suggest that rearrangements of non-coding sequences disturbing gene regulation may account for significant proportion of DSD cases.

The rhox homeobox gene family shows sexually dimorphic and dynamic expression during mouse embryonic gonad development.

Reproductive capacity is fundamental to the survival of all species. Consequently, much research has been undertaken to better understand gametogenesis and the interplay between germ cells and the somatic cell lineages of the gonads. In this study, we have analyzed the embryonic expression pattern of the X-linked gene family Reproductive homeobox genes on the X chromosome (Rhox) in mice. Our data show that eight members of the Rhox gene family are developmentally regulated in sexually dimorphic and temporally dynamic patterns in the developing germ cells during early gonadogenesis. These changes coincide with critical stages of differentiation where the germ cells enter either mitotic arrest in the testis or meiotic arrest in the ovary. Finally, we show that Rhox8 (Tox) is the only member of the Rhox gene family that is expressed in the somatic compartment of the embryonic gonads. Our results indicate that the regulation of Rhox gene expression and its potential function during embryogenesis are quite distinct from those previously reported for Rhox gene regulation in postnatal gonads.